This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have tested how well a simian-human immunodeficiency virus (SHIV) is transmitted across different mucosal surfaces in rhesus macaques that had no mucosal lesions and were challenged non-traumatically. This virus, termed SHIV-1157ipd3N4 (SHIV-C for short), is a unique virus generated by us;it encodes the envelope of an R5 HIV-1 clade C African isolate which was transmitted from mother to child (Song et al., Journal of Virology 2006;80:8729-38). SHIV-C was inoculated intrarectally, intravaginally, and orally into rhesus monkeys. We compared the 50% animal infectious doses for the different mucosal routes;virus transmission was easiest via the rectal route, followed by the intravaginal and lastly, the oral route. We also performed an intrarectal titration in rhesus monkeys of Chinese origin using the identical virus stock;4.5 times more virus was required to achieve systemic infection in Chinese macaques compared to their Indian counterparts. The relative transmissibility of SHIV-C across different mucosal surfaces was then compared to the relative risks of HIV-1 acquisition by humans exposed sexually via different routes. We made the intriguing finding that the hierarchy of mucosal SHIV-C transmission in experimentally inoculated rhesus macaques paralleled the relative risks of HIV-1 acquisition in humans depending in the route of mucosal exposure, with rectal being the riskiest, followed by the intravaginal, and finally, the oral route. Studies focused on whether a SHIV strain with CCR5 tropism is preferentially transmitted mucosally in rhesus monkeys are ongoing;animals were mucosally inoculated with a mix of R5 and X4 SHIVs.